It is known that lithium-containing drugs are effective drugs for feeling stabilization and antidepressant, so that they are used widely as feeling-stabilizer and antidepressant drug.
However, it is necessary to control the concentration of lithium in serum within a proper range when the lithium-containing drug is administrated to patients.
As feeling stabilizer, tablets of lithium carbonate (for oral administration) are generally prescribed together with another drug for bipolar disorder (circulatory psychosis) or anti-depressive drug. Lithium carbonate (Li2CO3) has such a characteristic that its administration effect is exhibited only when a concentration of lithium in blood arrives at nearly a lithium poisoning level. Therefore, the therapeutic drug monitoring (TDM) is prescribed to monitor the lithium concentration in blood when the drug is administrated, since a therapeutic range is very near to the poison level.
In practice, it is necessary to control or limit the concentration of lithium in a patient blood sample within a range of from 0.6 to 1.2 mEq/L in general. In fact, when the lithium concentration in serum is lower than 0.6 mEq/L, no antidepressive effect is expected. On the contrary, excess administration over 1.5 mEq/L concentration in plasma will result in the lithium poisoning. Overdose result in a fatal cause of symptom of poisoning including tremor, aralia, nystagmus, renal disturbance and convulsion. Therefore, when a sign of latently dangerous symptom of poisoning is observed, the treatment with lithium-containing drugs must be stopped and it is necessary to re-measure the concentration in plasma and to take measures to mitigate the lithium poisoning.
Thus, the lithium salt is an effective medicine in treatment of depression patients, but overdose thereof result in serious troubles. Therefore, when a lithium-containing anti-depressive drug is administered, it is indispensable to monitor the concentration of lithium in serum and to assure that the concentration is always kept in a limited range of from 0.6 to 1.2 mEq/L.
Therefore, it was requested to carry out the quantitative measurement of lithium in serum in the treatment of depression patient, and several liquid reagent compositions permitting colorimetric determination of lithium for clinical laboratory test have been developed.
Patent Document 1 discloses a reagent composition used to determine the concentration of lithium in a biological sample by using primary color body cryptideinofa.
Patent Document 2 discloses an analytical reagent which reacts with lithium ions, comprising a macrocyclic compound having a pyrrole ring and eight bromine (Br) atoms bonded at β position of the pyrrole ring.
Non-Patent Document 1 discloses that lithium ions can be detected by a compound in which all hydrogens bonded to carbons of tetraphenylporphyrin are replaced by fluorine.
Known lithium reagent compositions, however, have such demerits or problems that they are poisonous compositions, that drug substances are expensive or are not supplied stably and that most drug substances do not dissolve in water or, even soluble, and are deactivated in water, so that coloring reaction is very slow.
In Patent Document 2 which was developed to solve the above problems, a color developing technique can be used but it is necessary to dilute specimens because its sensibility is too high. Still more, this lithium reagent composition requires a pH range of over 11 and hence tends to be deteriorated with CO2 in air, so that the resulting measured data are not stable. Still more, in a range of over pH11, only sodium hydroxide and potassium hydroxide can be used to prepare practical concentrated aqueous solution and there is no other compounds which can be used actually, so that it is difficult to keep a constant pH value. Still more, these concentrated aqueous solutions are hazardous substances which are difficult to be handled, so that their use should be avoided. Du to these demerits, a special container is necessary and a large special equipment or installation is required in their handling, so that they are not suitable for general uses. Therefore, this technology has such a problem that it is difficult to apply to on-site monitoring and POCT (Point Of Care Testing).
In Patent Document 1, a compound which is completely different from the compound of this invention (which will be explained later) is used in a reagent composition for measuring a quantity of lithium. The compound of Patent Document 1 can be used only at pH 12. As stated above, in a range of over pH 11, there is no other practical concentrated aqueous solution than those of sodium hydroxide and of potassium hydroxide. And hence, the reagent composition of Patent Document 1 have no versatility because the above aqueous solution is hazardous substance which are difficult to be handled and a large special equipment or installation is required in their practical uses.
In the non-Patent Document 1, Koyanagi et al. disclose that lithium ions can be separated and detected by using F28 tetraphenylporphyrin. However, solvent extraction with oily poisonous chloroform is necessary to perform the separation and detection of lithium ions. Above all, direct determination of lithium in an aqueous solution could not be carried out without complicated pretreatment or handling.
Thus, there was such a problem that lithium ions in serum can't be measured rapidly and quantitatively in practical method. In fact, the quantitative measurement of lithium ions in aqueous solutions by using F28 tetraphenylporphyrin was difficult to be realized, so that the concentration of lithium ions could not be determined quantitatively in practical method.
The present inventors developed in Patent Document 3 (Japanese Patent No. 5,222,432) a reagent composition for lithium (“lithium reagent composition” hereafter), comprises a compound having a structure represented by the formula (I), as chelating agent:
in which all hydrogens bonded to carbons of a tetraphenylporphyrin are replaced by fluorine, a water-soluble organic solvent, a pH modifier and a stabilizer, and a method for measuring lithium by using the same, so that the lithium concentration in biological specimens and environmental liquid samples can be measured immediately and quantitatively by the convenient colorimeter or ultraviolet-visible light spectrophotometer. The present inventors provided also a lithium reagent composition which permits to determine the lithium concentration quantitatively and method and apparatus for measuring lithium ion using the same.